title: A C-type lectin receptor pathway is responsible for the pathogenesis of acute cyclophosphamide-induced cystitis in mice.
abstract: Hemorrhagic cystitis often arises after cyclophosphamide (CYP) administration. As yet, however, the mechanism involved in its pathogenesis is unknown. In this study, it was found that the Fc receptor γ chain (FcRγ)- caspase recruitment domain-containing protein 9 (CARD9)-dependent pathway rather than the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway is involved in the pathogenesis of acute CYP-induced cystitis in mice. Rapid and transient production of interleukin (IL)-6 and IL-1β was detected in the bladder at 4 hr, preceding IL-23 and IL-17A production and an influx of neutrophils, which reached a peak at 24 hr after injection. As assessed by weight, edema and neutrophil infiltration, cystitis was significantly attenuated in CARD9 knockout (KO) and FcRγKO mice, this attenuation being accompanied by impaired production of IL-1β, IL-6, IL-23 and IL-17A. The major source of IL-17A is the vesical γδ T cell population: IL-17AKO, CδKO and Tyk2KO mice showed little IL-17A production and reduced neutrophil infiltration in the bladder after CYP injection. These results suggest that FcRγ-CARD9-dependent production of proinflammatory cytokines such as IL-1β, IL-6, and IL-23 and the subsequent activation of IL-17A-producing γδ T cells are at least partly involved in the pathogenesis of acute CYP-induced cystitis in mice.
authors.affiliation: Division of Host Defense, Medical Institute of Bioregulation; Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka.
authors.forename: Takashi
authors.initials: T
authors.lastname: Dejima
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shibata
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D003520:Cyclophosphamide / Q000633:toxicity*; D003556:Cystitis / Q000139:chemically induced* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D016207:Cytokines; D037181:Lectins, C-Type; D017452:Receptors, IgG; D003520:Cyclophosphamide
keywords: caspase recruitment domain-containing protein 9; cystitis; interleukin-17A; γδ T cells